Diabetic complications from hyperglycemia affect the health of both type 1 and type 2 diabetics. There are several theories to explain the development of complications. The fact that inhibitors of aldose reductase prevent complications in experimental diabetes suggests a central role for this enzyme. The central hypothesis of this study is that aldose reductase is involved in the development of all diabetic complications and that the level of expression of aldose reductase is the determining factor in the development of complications. A second hypothesis is that human aldose reductase differs significantly from other aldose reductases and that animal aldose reductases are not good models for human aldose reductase. The objectives of this proposal are: 1) to develop an integrative model of diabetic complications that has a central role for aldose reductase and that accommodates the experimental evidence that supports current theories of complications; and 2) to conduct a detailed kinetic and chemical study of human aldose reductase with emphasis on the inhibitor binding site. The Specific Aims of this proposal focus on human aldose reductase and include enzyme, chemical, cellular and tissue studies. These studies are designed to test the idea that the complication of diabetes result both from reactions involving glucose and from reactions involving acetol and methylglyoxal, which are derived from glucose. Glucose, methylglyoxal and acetol are substrates for aldose reductase. In addition, all of these compounds react nonenzymatically with proteins. The longterm goals are: 1) to establish an enzymological foundation to our understanding of human aldose reductase that will contribute to the development of new aldose reductase inhibitors; and 2) to develop a paradigm for predicting which diabetics will develop complications and will benefit from therapy with aldose reductase inhibitors.